The present invention provides uniform distribution of the active component in a solid composition, high stability and improved flowability of the solid pharmaceutical composition. Due to improved flowability the compositions suggested in the invention could be used on automatic equipment.
2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in the form of free base or in the form of pharmaceutically acceptable salt, for example, hydrochloride, represents a S1P receptor modulator. Sphingosine-1 phosphate (hereinafter “S1P”) is a natural blood serum lipid. Presently there are eight known S1P receptors, namely from Lysophospholipid edg1 to edg8 [http://integrity.thomson-pharma.com]. Modulators or agonists S1P are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives, e.g. a compound comprising a group of the general formula A [WO 2007/021166],

wherein Z represents H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl; phenyl, substituted with OH; C1-6alkyl, substituted with 1-3 substituents selected from the group consisting of halogen, C3-8cycloalkyl, phenyl and phenyl substituted with OH, or CH2—R4z, wherein R4z is OH, acyloxy or a residue of a formula A1,

wherein Z1 is a direct bond or O, preferably O; each of R5z and R6z, independently, is H, or C1-4 alkyl, optionally substituted with 1, 2 or 3 halogen atoms;
R1z is OH, acyloxy or a residue of formula A, and each of R2z and R3z, independently, is H, C1-4 alkyl or acyl.
S1P receptor modulators are the compounds which act as agonists of one or more sphingosine-1 phosphate receptors, e.g. from S1P1 to S1P8. Agonist binding to S1P receptor may e.g. cause dissociation of intracellular heterotrimeric G-proteins into Gα-GTP and Gβy-GTP, and/or increase phosphorylation of the agonist-accupied receptor and activation of downstream signaling pathways/kinases.
As can be seen from various review, the more preferable modulators or agonists of S1P receptors are compounds of the general formula B [EP 627406A1],

wherein:
R1 is a straight or branched C12-22chain, which may have a bond or a heteroatom selected from a double bond, a triple bond, O, S, NR6, wherein R6 is H, C1-4alkyl, aryl-C1-4alkyl, acyl, C1-4alkoxycarbonyl, and carbonyl, and/or
which may have such a substituent as C1-4alkoxy, C2-4alkenyloxy, C2-4alkynyloxy, aryl-C1-4alkoxy, acyl, C1-4alkylamino, C1-4alkylthio, acylamino (C1-4alkoxy)carbonyl, (C1-4alkoxy)-carbonylamino, acyloxy, (C1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxyimino, hydroxyl or carboxy; or
R1 represents
phenylalkyl, wherein alkyl is a straight or branched (C6-20)carbon chain; or
phenylalkyl, wherein alkyl is a straight or branched (C1-30)carbon chain, wherein the said phenylalkyl is substituted with
straight or branched (C6-20)carbon chain, optionally substituted with halogen,
straight or branched (C6-20)alkoxy chain, optionally substituted with halogen,
straight or branched (C6-20)alkenyloxy,
phenyl-C1-14alkoxy, halogenphenyl-C1-14alkoxy, phenyl-C1-14alkoxy-C1-14alkyl, phenoxy-C1-4alkoxy or phenoxy-C1-14alkyl,
cycloalkyl substituted with C6-20alkyl,
heteroaralkyl substituted with C6-20alkyl,
heterocyclic C6-20alkyl or heterocyclic alkyl substituted with C2-20alkyl,
and wherein the alkyl moiety may have:
in the carbon chain a bond or a heteroatom selected from a double bond, a triple bond, O, sulfinyl, sulfonyl or NR6, wherein R6 is as defined above, and
as a substituent C1-4alkoxy, C2-4alkenyloxy, C2-4alkynyloxy, aryl-C1-4alkoxy, acyl, C1-4alkylamino, C1-4alkylthio, acylamino, (C1-4alkoxy)carbonyl, (C1-4alkoxy)carbonylamino, acyloxy, (C1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or carboxy; and
each of R2, R3, R4 and R5, independently, is H, C1-4alkyl or acyl, or
a pharmaceutically acceptable salt or hydrate thereof.
In particular, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol of formula 1 (fingolimod) in free form or in the form of pharmaceutically acceptable salt, e.g. hydrochloride, is an immune modulator which causes redistribution of lymphocytes from blood flow into secondary lymphoid tissue that leads to immune suppression. It is widely used for prophylaxis and treating rejection of new organs or transplanted tissue, e.g. for treating heart transplant recipient, lungs, heart-lung, liver, kidney, pancreatic, skin or corneal transplants; and for prophylaxis of graft-versus-host diseases, such as sometimes happen to be after bone-marrow transplantation; for prophylaxis and treating autoimmune diseases, or inflammatory conditions, such as multiple sclerosis, arthritis (for example, rheumatoid arthritis), inflammatory bowel diseases, hepatitis and so on; for prophylaxis and treating viral myocarditis and viral diseases including hepatitis and HIV [as it was mentioned in, e.g. U.S. Pat. No. 5,604,229, WO 1997/024112, WO 2001/001978, U.S. Pat. No. 6,004,565, U.S. Pat. No. 6,274,629, and JP-14316985].

In spite of the fact that 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, first of all in the form of salt, is water soluble, immediately after preparation of the solution or in the course of its storage the crystalline precipitate of this compound is formed. So, a pharmaceutical solution could be preferably used immediately or within short period of time after preparation, e.g. within 4 hours.
It has been determined that addition of cyclodextrins to water solutions of [U.S. Pat. No. 6,476,004] this compound reduces effectively the development of crystalline precipitate, however application of cyclodextrins is limited by their high cost and established standards. Semi-aqueous composition of the compound comprising ethanol and polyethylene glycol is described in EP 0627406. In spite of the fact that crystalline precipitate does not form in semi-aqueous solutions, there are some problems at intravenous administration of the compositions, such as local irritation and hemolysis because of the high concentration of ethanol and polyethylene glycol containing in the composition. There are known various types of liquid concentrates comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol [WO 2007/021666 or RU 2402324], predominantly with propylene glycol and, optionally, glycerin. In addition, there is a limitation for medicaments for oral administration to pediatric patients in the sense of smaller number of suitable inert fillers, that is, such composition should preferably be without alcohol.
Thus, the more preferable are solid pharmaceutical compositions comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol.
It is known the use of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in solid pharmaceutical compositions, for example, in WO 2009/048993, wherein fillers are selected from lactose monohydrate, anhydrous lactose, corn starch, mannitol, xylitol, sorbitol, sucrose, microcrystalline cellulose, e.g., Avicel PH 101, dicalcium phosphate, maltodextrin, gelatin; binders are selected from HPMC, L-HPC, Povidone, HPC; disintegrators are selected from corn starch, crospovidone, sodium croscarmellose, sodium carboxymethyl starch, pre-gelatinized starch, calcium silicate; lubricants are selected from hydrogenated castor oil, glyceryl behenate, magnesium stearate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, sodium stearyl fumarate, etc.
It is known the use of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in solid pharmaceutical compositions, for example, in WO 2008/037421, where polymer resins and one or more metal oxides were introduced into composition.
It is known the use of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in solid pharmaceutical compositions, for example, in RU 2426555, where polyethylene glycol 300 and polysorbate 80 are used in the compositions for treating cancer.
It is also known the use of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in solid pharmaceutical compositions, for example, in RU 2358716, where a pharmaceutical composition suitable for oral administration comprises 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY-720), sugar alcohol represented by mannitol, magnesium stearate as a lubricant, which is intended for use in the manufacture of a medicament for prophylaxis or treating rejection of new organs or transplant tissue, graft versus host reaction, autoimmune diseases, inflammatory conditions, viral myocarditis and viral diseases related to viral myocarditis, for use in the manufacture of a medicament for treating multiple sclerosis.
When automatic filling machines are used the substances must exhibit some definite physical-chemical and technological properties, such as:                definite size and shape of particles;        uniformity of particle size;        homogeneity of mixing;        flowability (flow);        moisture content;        ability to be compactly formed under pressure.(Industrial Technology of medicaments. Vol. 2 ed. Chueshova V. I., 2002, p. 407-408).        
On retention of sufficiently high parameters of bioavailability of the active component, the disadvantage of the above known solid pharmaceutical compositions of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol is insufficiently high flowability, that does not allow effectively use modern automatic equipment.